Methylation is an epigenetic mechanism that can both positively and negatively regulate gene expression. Although methylation serves a critical role in driving many cell-specific and tissue- specific functions, it is now well-established that some, bu not all, epigenetic modifications of DNA may also occur in response to changes in the environment. Importantly, these changes can stably alter gene expression in a manner that may influence metabolism, behavior, and ultimately overall health. Exercise has been shown to have positive effects on both physical and mental health outcomes but the exact molecular mechanism driving stable changes in health following exercise are not well known. Our initial examination of methylation states before and after exercise training has provided evidence that methylation is labile to physiologic changes associated with exercise training, and that this liability may be a function of genomic background. We have performed extensive research characterizing over 3,000 individuals undergoing aerobic exercise training using a carefully-controlled and documented aerobic exercise regimen. We have collected multiple parameters related to exercise tolerance, including heart rate, intensity, duration, and total exercise exposure. In addition, we have both DNA and RNA from approximately 1,500 individuals, both pre- and post-exercise. In this project, we plan to characterize both whole genome methylation and gene expression in sedentary individuals' pre- and post-exercise training in order to identify the primary targets of alterations in gene regulation. This research has the potential to reveal new insights into the mechanisms that influence the ability to respond to or maintain health behaviors like physical activity.